This project is based on the hypothesis that microglia, activated by contact with neuritic and core senile plaques, contribute to the neuronal injury associated with Alzheimer's disease (AD). The investigator's previous work indicated that beta-amyloid peptide 1-42 (Abeta 1-42) found in senile plaques provides a signal to release microglial cytotoxins. A body of evidence now suggests that receptors found on microglial surfaces help to mediate this neurotoxic cascade. The interactions among Abeta 1-42 and microglial membrane sites are the focus of the proposed investigation. Using competition studies coupled neurotoxic assays, they have identified portions of Abeta that bind to microglia during induction of neuron-killing. Some of these peptides will be used as tools to isolate Abeta binding proteins from mononuclear phagocytes and to identify membrane components that mediate Abeta activation of microglia. The investigators have also found that apolipoprotein E (apoE) influences the ability of Abeta to interact with microglia. Another aim of this project will examine the ability of apoE to serve as an immuno-regulator of neurotoxic microglia. Experimental strategies to assess protein-protein interactions will include study of specific Abeta peptide fragments and selective modifications of apoE amino acid residues. Abeta complex formation with microglia is a fundamentally important step that initiates AD immunopathology. Identification of specific microglial membrane proteins which interact with Abeta and the delineation of a role for apoE in this immune cascade offer important insights into immune mechanisms of CNS disease. Successful completion of this project will impact upon the development of drug targets for treatment of AD.